P(1) Glutamine isosteres in the design of inhibitors of 3C/3CL protease of human viruses of the Pisoniviricetes class

Viral infections are one of the leading causes of acute morbidity in humans and much endeavour has been made by the synthetic community for the development of drugs to treat associated diseases. Peptide-based enzyme inhibitors, usually short sequences of three or four residues, are one of the classes of compounds currently under development for enhancement of their activity and pharmaceutical properties. This review reports the advances made in the design of inhibitors targeting the family of highly conserved viral proteases 3C/3CL(pro), which play a key role in viral replication and present minimal homology with mammalian proteases. Particular focus is put on the reported development of P(1) glutamine isosteres to generate potent inhibitors mimicking the natural substrate sequence at the site of recognition.’